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From: TSS ()
Subject: Kuru prions and sporadic Creutzfeldt–Jakob disease prions have equivalent transmission properties in transgenic and wild-type mice
Date: March 4, 2008 at 1:28 pm PST

Kuru prions and sporadic Creutzfeldt–Jakob disease prions have equivalent transmission properties in transgenic and wild-type mice


Jonathan D. F. Wadsworth, Susan Joiner, Jacqueline M. Linehan, Melanie Desbruslais, Katie Fox, Sharon Cooper,
Sabrina Cronier, Emmanuel A. Asante, Simon Mead, Sebastian Brandner, Andrew F. Hill*, and John Collinge†

Medical Research Council Prion Unit and Department of Neurodegenerative Disease, University College London Institute of Neurology, National Hospital for
Neurology and Neurosurgery, Queen Square, London WC1N 3BG, United Kingdom

Communicated by Charles Weissmann, The Scripps Research Institute, Jupiter, FL, January 10, 2008 (received for review October 10, 2007)


Kuru provides our principal experience of an epidemic human prion
disease and primarily affected the Fore linguistic group of the
Eastern Highlands of Papua New Guinea. Kuru was transmitted by
the practice of consuming dead relatives as a mark of respect and
mourning (transumption). To date, detailed information of the
prion strain type propagated in kuru has been lacking. Here, we
directly compare the transmission properties of kuru prions with
sporadic, iatrogenic, and variant Creutzfeldt–Jakob disease (CJD)
prions in Prnp-null transgenic mice expressing human prion protein
and in wild-type mice. Molecular and neuropathological data from
these transmissions show that kuru prions are distinct from variant
CJD and have transmission properties equivalent to those of
classical (sporadic) CJD prions. These findings are consistent with
the hypothesis that kuru originated from chance consumption of
an individual with sporadic CJD.


snip...


Discussion

In the present study, we have compared the transmission properties
of kuru prions with sporadic, iatrogenic, and variant CJD
prions in transgenic mice expressing human PrP valine 129 and
in wild-type mice. These data establish that kuru prions have
transmission properties equivalent to those of classical CJD
prions and are distinct from vCJD prions. In agreement with this
finding, the molecular strain types of PrPSc seen in kuru brain
correspond to those seen in classical CJD rather than the distinct
PrPSc types seen in vCJD or inherited prion disease. These
collective data establish that kuru and classical CJD prions have
closely similar prion strain properties and are consistent with the
hypothesis that kuru originated from chance consumption of an
individual with sporadic CJD (43).
Human prion diseases with distinct etiologies are associated
with a range of clinical presentations that are now seen as
clinicopathological syndromes rather than individual disease
entities (4, 55, 56). The central clinical feature of kuru is
progressive cerebellar ataxia, and, in sharp contrast to sporadic
CJD, dementia is a late and less prominent feature. A prodrome
and three clinical stages consisting of an ambulatory stage, a
sedentary stage, and a tertiary stage have been described in ref.
20. In this regard, the natural history of kuru is more reminiscent
of vCJD in which early symptoms of distal sensory disturbance,
joint pains, and psychiatric and behavioral changes are common
before forthright dementia (4, 23, 25, 28). Despite these similarities
in early clinical presentation, the molecular and neuropathological
features of kuru are distinct from vCJD. In contrast
to the occurrence of abundant florid PrP plaques that are the
neuropathological
changes seen in kuru lie within the spectrum of
those seen in sporadic CJD. Unicentric PrP plaques, however,
are unusually prominent and widespread (58, 59). This pattern
of neuropathology most closely resembles a relatively rare
subtype of sporadic CJD associated with long clinical duration
and PRNP codon 129 heterozygosity in which kuru-type PrP
plaques are also observed (10, 11, 46).
Although PrP plaques are not a prominent feature of the most
common subtypes of sporadic CJD, where diffuse synaptic PrP
deposition predominates (10, 11, 46, 60), kuru-type plaques are
a notable feature of iatrogenic CJD resulting from peripheral
inoculation, most conspicuously after cadaveric pituitaryderived
hormone exposure (61). This form of iatrogenic CJD
also typically presents with a progressive cerebellar syndrome
reminiscent of kuru, whereas cases of iatrogenic CJD arising
from intracerebral or ocular inoculation usually manifest clinically
as sporadic CJD, with a rapidly progressive dementia
(62–65). These observations suggest that cerebellar onset and
subsequent neuropathological changes may be determined in
part by a peripheral route of exposure. The similarity of prion
strain type in kuru and sporadic CJD demonstrated here now
clearly suggests that peripheral routes of infection (predominantly
dietary), rather than prion strain type, may be an important
determinant of the clinicopathological phenotype of kuru.
In this regard, the etiology of sporadic CJD remains unclear,
although its remarkably uniform worldwide incidence and apparently
random distribution suggest involvement of a stochastic
process such as somatic PRNP mutation (2, 48, 66, 67). It is thus
possible that part of the phenotypic and neuropathological
heterogeneity seen in sporadic CJD could be related to peripheral
versus central initiation of prion replication.
Aside from route of exposure, additional factors may also
influence the neuropathology and clinical features of kuru. A
number of genetic modifiers of prion disease have been mapped
in mice (16, 17). Although the genes responsible for mouse
incubation time quantitative trait loci have not yet been identified,
orthologous human genes are likely to be globally polymorphic
with significant differences within and between Europe
and the Fore. Furthermore, age is an important determinant of
youth may be associated with an atypical sporadic CJD neuropathology
(70). The marked difference in mean age of kuru and
sporadic CJD patients might thus account for some of the
neuropathological differences that distinguish kuru from the
majority of sporadic CJD cases.
Our finding that kuru prions and vCJD prions have very
different transmission properties supports previous molecular
(9, 45–47, 49, 50), neuropathological (25, 57, 58), and transmission
(14, 15, 26, 27) data indicating that vCJD is a highly distinct
human prion strain. The pathogenesis of vCJD differs significantly
from that of other forms of human prion disease. PrPSc is
readily detectable in lymphoreticular tissues in vCJD and not in
classical CJD or inherited prion disease (29, 32, 47, 71–76).
Because kuru, iatrogenic CJD, and vCJD are caused by a
peripheral route of exposure to infectious prions, it is possible
that extensive lymphoreticular pathogenesis may result from this
common route of exposure. However, the fact that tonsillar prion
infection has not been detected in iatrogenic CJD associated
with use of human cadaveric derived pituitary hormone (72, 75)
or kuru (unpublished data) suggests that the distinct peripheral
pathogenesis of vCJD is determined by prion strain type alone
rather than route of infection.
Although distinct from the vCJD prion strain, kuru is critically
important as our only precedent of an orally acquired human
prion disease epidemic. There remain striking parallels between
the two outbreaks in terms of their clinical features, restricted
temporal and geographic distribution, and the long and variable
incubation times observed. Profound disease susceptibility is
conferred by PRNP codon 129 in both diseases (4, 5, 15, 22).
Because mouse models of prion disease demonstrate the importance
of a small number of non-Prnp genetic factors in control
of incubation time, it will be important to understand how the
orthologous human genes modify susceptibility or incubation to
both kuru and vCJD. ...snip...end...tss


Fig. 2. Molecular strain typing of human prion transmissions to mice. Immunoblots of proteinase K-digested brain homogenates from wild-type mice, human
patients, or transgenic mice analyzed by enhanced chemiluminescence with anti-PrP monoclonal antibodies ICSM35 (A) or 3F4 (B–D) are shown. The provenance of each brain sample is designated above each lane, and the type of human PrPSc detected in each sample (B–D) is designated below. (A) Transmission of vCJD prions (I344) and sporadic CJD prions (I764) to FVB/NHsd mice. (B) Transmission of vCJD prions (I348) to 129VV Tg152 mice. (C) Transmission of sporadic CJD prions with type 3 PrPSc (I4855) and kuru prions with type 3 PrPSc (I516) to 129VV Tg152 mice. (D) Transmission of kuru prions with type 2 PrPSc (I518) to 129VV Tg152 mice revealing a change in molecular strain type.


Fig. 3. Neuropathological analysis of transgenic mouse brain. Equivalent patterns of neuropathology are seen in 129VV Tg152 mice that propagate type 3 PrPSc
after primary transmission of kuru prions or sporadic CJD prions that are distinct from 129VV Tg152 mice that propagate type 5 PrPSc after primary transmission
of vCJD prions. Sketches represent the regional distribution of abnormal PrP deposition in transgenic mouse brain: diffuse synaptic PrP deposition (bars) and PrP
plaques (circles). The bottom images show PrP immunohistochemistry with ICSM 35 (from the areas delineated by the blue boxes in the sketches) demonstrating
nonflorid PrP plaques in the corpus callosum and diffuse synaptic PrP deposition in the thalamus. (Scale bar, bottom images: 100 m.)

Wadsworth et al. PNAS  March 11, 2008  vol. 105  no. 10  3887


Materials and Methods


snip...end...TSS
www.pnas.orgcgidoi10.1073pnas.0800190105 Wadsworth et al.
http://www.pnas.org/cgi/reprint/0800190105v1.pdf

well, i guess this just tells ya not to eat your neighbor, (besides the fact my mom died from the hvCJD,
my neighbors mom also died from sCJD, both cases confirmed). OR just maybe the atypical h-BASE,
which is very similar to some sporadic CJD pathologically, via consumption of h-base atypical BSE USA
CATTLE, is the cause of some of these sporadic CJD cases in the USA ??? or, what about the l-base
and the TME ??? it's getting dicey now folks, OR maybe a little mix of the NOR-98 atypical scrapie (now
documented in 5 different states). hmmm, i am thinking Mission, Texas. ALSO, what about all those
downers i.e. 95%+ deadstock downer cow feeder i.e. TME mink outbreaks. OR, what a minute now, i am
not through, what about the CWD and very likely potential there for multiple strains. it's all coming together
folks, the USA is a smorgasbord for all kinds of human and animal TSE, via many different routes and sources.
thus, the BSE MRR policy was born, the legal trading of all strains of TSE, globally, all for a buck $$$


PROBLEMS SOLVED, ''MISSION ACCOMPLISHED'' ! GOD BLESS AMERICA !


WE already knew that sporadic CJD would transmit to primate by non-forced oral consumption ;

Oral transmission of kuru, Creutzfeldt-Jakob disease, and scrapie to nonhuman primates.Gibbs CJ Jr, Amyx HL, Bacote A, Masters CL, Gajdusek DC.
Kuru and Creutzfeldt-Jakob disease of humans and scrapie disease of sheep and goats were transmitted to squirrel monkeys (Saimiri sciureus) that were exposed to the infectious agents only by their nonforced consumption of known infectious tissues. ...

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=6997404&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus

Phenotypic Similarity of Transmissible Mink Encephalopathy in Cattle and L-type Bovine Spongiform Encephalopathy in a Mouse Model
Volume 13, Number 12–December 2007
Research

http://transmissible-mink-encephalopathy.blogspot.com/


3.57 The experiment which might have determined whether BSE and scrapie were
caused by the same agent (ie, the feeding of natural scrapie to cattle) was
never undertaken in the UK. It was, however, performed in the USA in 1979,
when it was shown that cattle inoculated with the scrapie agent endemic in
the flock of Suffolk sheep at the United States Department of Agriculture in
Mission, Texas, developed a TSE quite unlike BSE. 32 The findings of the
initial transmission, though not of the clinical or neurohistological
examination, were communicated in October 1988 to Dr Watson, Director of the
CVL, following a visit by Dr Wrathall, one of the project leaders in the
Pathology Department of the CVL, to the United States Department of
Agriculture. 33 The results were not published at this point, since the
attempted transmission to mice from the experimental cow brain had been
inconclusive. The results of the clinical and histological differences
between scrapie-affected sheep and cattle were published in 1995. Similar
studies in which cattle were inoculated intracerebrally with scrapie inocula
derived from a number of scrapie-affected sheep of different breeds and from
different States, were carried out at the US National Animal Disease Centre.
34 The results, published in 1994, showed that this source of scrapie agent,
though pathogenic for cattle, did not produce the same clinical signs of
brain lesions characteristic of BSE.

http://www.bseinquiry.gov.uk/


The findings of the initial transmission, though not of the clinical or
neurohistological examination, were communicated in October 1988 to Dr
Watson, Director of the CVL, following a visit by Dr Wrathall, one of the
project leaders in the Pathology Department of the CVL, to the United States
Department of Agriculture. 33

http://www.bseinquiry.gov.uk/files/yb/1988/10/00001001.pdf


12/10/76
AGRICULTURAL RESEARCH COUNCIL
REPORT OF THE ADVISORY COMMITTE ON SCRAPIE
Office Note
CHAIRMAN: PROFESSOR PETER WILDY


snip...


A The Present Position with respect to Scrapie
A] The Problem

Scrapie is a natural disease of sheep and goats. It is a slow
and inexorably progressive degenerative disorder of the nervous system
and it ia fatal. It is enzootic in the United Kingdom but not in all
countries.

The field problem has been reviewed by a MAFF working group
(ARC 35/77). It is difficult to assess the incidence in Britain for
a variety of reasons but the disease causes serious financial loss;
it is estimated that it cost Swaledale breeders alone $l.7 M during
the five years 1971-1975. A further inestimable loss arises from the
closure of certain export markets, in particular those of the United
States, to British sheep.

It is clear that scrapie in sheep is important commercially and
for that reason alone effective measures to control it should be
devised as quickly as possible.

Recently the question has again been brought up as to whether
scrapie is transmissible to man. This has followed reports that the
disease has been transmitted to primates. One particularly lurid
speculation (Gajdusek 1977) conjectures that the agents of scrapie,
kuru, Creutzfeldt-Jakob disease and transmissible encephalopathy of
mink are varieties of a single "virus". The U.S. Department of
Agriculture concluded that it could "no longer justify or permit
scrapie-blood line and scrapie-exposed sheep and goats to be processed
for human or animal food at slaughter or rendering plants" (ARC 84/77)"
The problem is emphasised by the finding that some strains of scrapie
produce lesions identical to the once which characterise the human
dementias"

Whether true or not. the hypothesis that these agents might be
transmissible to man raises two considerations. First, the safety
of laboratory personnel requires prompt attention. Second, action
such as the "scorched meat" policy of USDA makes the solution of the
acrapie problem urgent if the sheep industry is not to suffer
grievously.

snip...

76/10.12/4.6

http://www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf


SCRAPIE DOCUMENTED IN CLINICAL SUSPECT GOAT, WITH TWO MORE DOCUMENTED
IN SAME BIRTH HERD OF CLINICAL CASE

http://nor-98.blogspot.com/2008/03/fw-bse-l-scrapie-documented-in-clinical.html


ATYPICAL NOR-98 SCRAPIE LOCATION UPDATE ON 5 DOCUMENTED CASES THIS YEAR ;


The flocks of origin are WY, CO, CA, IN, and MN.


personal communication USDA et al. ...TSS

snip...

INFECTED AND SOURCE FLOCKS AS of August 31, 2007, there were 33 scrapie
infected and source flocks with open statuses (Figure 3). Five new source
flocks and one new infected flock were reported n August (Figure 4) with a
total of 64 reported for FY 2007(Figure 5).


snip...


IN FY 2007 TWO FIELD CASES, ONE VALIDATION CASE, AND TWO RSSS CASES WERE
CONSISTENT WITH NOR-98 SCRAPIE. ...


(BRINGS A TOTAL OF 5 NOR-98 CASES DOCUMENTED IN 2007 IN USA. ...TSS)


http://www.aphis.usda.gov/animal_health/animal_diseases/scrapie/downloads/monthly_scrapie_rpt.pps


FULL TEXT ;

http://nor-98.blogspot.com/


CHRONIC WASTING DISEASE

http://chronic-wasting-disease.blogspot.com/


ANIMAL HEALTH REPORT 2006 (BSE h-BASE EVENT IN ALABAMA, Scrapie, and CWD)

http://animalhealthreport2006.blogspot.com/

CREUTZFELDT JAKOB DISEASE MAD COW BASE UPDATE USA

http://cjdmadcowbaseoct2007.blogspot.com/

CREUTZFELDT JAKOB DISEASE MAD COW BASE UPDATE USA

http://cjdmadcowbaseoct2007.blogspot.com/2008/02/evaluation-of-human-transmission-risk.html


Friday, February 8, 2008

Creutzfeldt Jakob Disease Delaware UPDATE

http://cjdmadcowbaseoct2007.blogspot.com/2008/02/creutzfeldt-jakob-disease-delaware.html


CJD TEXAS

http://cjdtexas.blogspot.com/


Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States

http://cjdusa.blogspot.com/

Creutzfeldt Jakob Disease

http://creutzfeldt-jakob-disease.blogspot.com/

Creutzfeldt-Jakob Disease, Prion Protein Gene Codon 129VV, and a Novel PrPSc
Type in a Young British Woman


http://creutzfeldt-jakob-disease.blogspot.com/2008/01/creutzfeldt-jakob-disease-prion-protein.html


Friday, January 11, 2008

CJD HUMAN TSE REPORT UK, USA, CANADA, and Mexico JANUARY 2008


http://cjdmadcowbaseoct2007.blogspot.com/2008/01/cjd-human-tse-report-uk-usa-canada-and.html


Sunday, December 16, 2007

Risk factors for sporadic Creutzfeldt-Jakob disease

Published Online: 11 Dec 2007


http://creutzfeldt-jakob-disease.blogspot.com/2007/12/risk-factors-for-sporadic-creutzfeldt.html

http://creutzfeldt-jakob-disease.blogspot.com/2008/01/risk-factors-for-sporadic-creutzfeldt.html


Monday, December 31, 2007

Risk Assessment of Transmission of Sporadic Creutzfeldt-Jakob Disease in Endodontic Practice in Absence of Adequate Prion Inactivation

http://creutzfeldt-jakob-disease.blogspot.com/2007/12/risk-assessment-of-transmission-of.html


Friday, January 25, 2008

January 2008 Update on Feed Enforcement Activities to Limit the Spread of
BSE

http://madcowspontaneousnot.blogspot.com/2008/01/january-2008-update-on-feed-enforcement.html


http://madcowspontaneousnot.blogspot.com/


BSE BASE MAD COW TESTING TEXAS, USA, AND CANADA

http://madcowtesting.blogspot.com/


Sunday, February 17, 2008
Release No. 0046.08

Statement by Secretary of Agriculture Ed Schafer Regarding Hallmark/Westland Meat Packing Company Two Year Product Recall

USDA Press Office (202) 720-4623


http://cjdmadcowbaseoct2007.blogspot.com/2008/02/release-no-004608-statement-by.html


NON-AMBULATORY (DOWNER) COW

http://downercattle.blogspot.com/


Wednesday, February 27, 2008
BEEF RECALL NATIONWIDE - SCHOOL LUNCH PROGRAM UPDATE


http://downercattle.blogspot.com/2008/02/beef-recall-nationwide-school-lunch.html

CJD QUESTIONNAIRE

http://cjdquestionnaire.blogspot.com/


Terry S. Singeltary Sr.
P.O. Box 42
Bacliff, Texas USA 77518






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